This invention relates to organopolysiloxane molding composition drug excipients having a regular, uniform and prolonged drug dispensation rate, the use of such carriers for the production of medicinal agents and the medicinal agents prepared therefrom.
Organopolysiloxane elastomers in general are known to be suitable carrier materials for depot drug preparations providing long-term treatment in a living organism, since they are neither degraded nor resorbed by the organism and show a good tissue compatibility as compared to other synthetic polymers.
Nonionic, lipid-soluble medicaments enclosed in organosiloxane elastomers and in organosiloxane-resin-reinforced organopolysiloxane elastomers are released with a delay from the carrier material, e.g. as has been described by Kincl et al, Steroids 11(5) : 675-680 (1968); Dzuik and Cook, Endocrinology 78:208-211 (1966); Carrett and Chemburkar, J. Pharm. Sci. 57:1401-1409 (1968); and DOS (German Unexamined Laid-Open Application) 2,158,226.
The use of solid organopolysiloxane elastomers and organopolysiloxane elastomers reinforced with an organosiloxane resin as drug excipients with a controlled drug release of medicament is known and has been described, inter alia, in U.S. Pat. No. 3,279,996; British Pat. No. 998,794; DOS's 1,467,861; 1,900,196; 1,912,343; and 2,158,226.
The following organopolysiloxane elastomer raw materials are customary for the preparation of medication carriers:
1. Thermosetting organopolysiloxanes to be vulcanized with peroxide curing catalysts, e.g. benzoyl peroxide or di-p-chlorobenzoyl peroxide at temperatures of about 200.degree. C. and requiring a heat aftertreatment, e.g. those described in U.S. Pat. Nos. 2,541,137; 2,723,966; 2,863,846; 2,890,188 and 3,002,951.
2. Hydroxyl-terminated organopolysiloxanes of the RTV (room temperature vulcanizing) type have been employed which harden to elastomers at room temperature after the addition of cross-linking agents in the presence of curing catalysts and under the atmospheric humidity. Typical curing catalysts are metallic salts of carboxylic acids, preferably tin salts, e.g. tin (II) octoate and tin (II)-2-ethylhexanoate.
3. Single-component silicone rubber compositions which are cured at room temperature under atmospheric humidity without any further additives are also known. These singlecomponent compositions contain primarily organopolysiloxanes with two terminal-positioned hydrolyzable acyloxy groups, e.g. acetoxy; the acyloxy groups are hydrolyzed under atmospheric humidity to form trifunctional siloxane units which cross-link the polymer into a cured elastomer. Such organopolysiloxanes are described, e.g., in U.S. Pat. Nos. 2,927,907 and 3,035,016 and in British Pat. Nos. 798,669 and 804,199.
These latter polysiloxane elastomers are obtained by thermosetting linear organopolysiloxanes and are utilized only in the preformed vulcanized condition to prepare drug excipients. Vulcanization of organopolysiloxane containing the drug is impossible, since almost all useful drugs are unstable either at the required high vulcanizing temperature and/or in the presence of peroxide catalysts.
4. Two-component dimethylpolysiloxane compositions, platinum-catalyzed at room temperature or under slightly elevated temperature and capable of addition cross-linking are also suitable as a carrier material for long-term delayed release depot drugs, e.g. see U.S. Pat. Application Ser. No. 444,886 filed Feb. 22, 1974 and corresponding DOS 2,158,226. In most cases, dimethylpolysiloxanes are used having one vinyl group on the chain end; the vinyl groups, however, need not be terminal-positioned. As the cross-linking agent, a methyl hydrogen polysiloxane is used having the general formula ##STR1## which can optionally also contain dimethylpolysiloxane groupings, but which contains at least 3 H atoms in the molecule as described in "Chemiker-Zeitung" (Chemist's News) 97(4):178-179 (1973).
According to DOS 2,158,226, LTV silicone rubber two-component compositions of the type disclosed in U.S. Pat. No. 2,823,218 consisting of (a) 85-95% by weight linear dimethylpolysiloxane containing maximally 0.5 molar percent methylvinylsiloxane units and having a molecular weight of 20,000-50,000, with (b) correspondingly 15-5% by weight of a dimethylpolysiloxane having an average molecular weight of 500-1,000, containing preferably 2 or 3 Si-H linkages per molecule, catalyzed with platinum or platinum compounds such as hexachloroplatinic acid, are utilized as medication carriers for depot drug preparations for the long-term treatment in a living organism.
Similarly suitable as a carrier material for the preparation of long-term depot drug compositions, according to DOS 2,158,226, are platinum-catalyzed dimethylpolysiloxane two-component compositions which are capable of addition cross-linking and consist of 85-89% by weight of the aforementioned dimethylpolysiloxane containing maximally 0.5 molar percent of methylvinylsiloxane units, 5-10% by weight of the aforementioned dimethylpolysiloxane with Si-H bonds, and 5-10% of a dimethylpolysiloxan resin having no more than 1.2 molar percent of methylvinylsiloxane units as an auxiliary cross-linking agent, catalyzed with a platinum compound.
The use of such dimethylpolysiloxane two-component compositions capable of additional cross-linking as medication carriers for depot drug forms often fails due to the fact that these compositions can be converted into usable vulcanizates only in admixture with medicaments which are chemically almost saturated substances. Olefinically and especially multiolefinically or acetylenically unsaturated compounds, e.g. 3-methoxy-19-nor-17.alpha.-pregna-1,3,5(10)-trien-20-yn-17-ol (mestranol) and ethynylestradiol, in admixture with these LTV silicone rubber two-component compositions prevent vulcanization of the silicone base.